Examples of prior art references which relate to an insulin sensitizer or an anorectic are mentioned below.
1) JP-A H9(1997)-67271 describes "a pharmaceutical composition an insulin sensitivity enhancer in combination with at least one member selected from the group consisting of .alpha.-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide, a statin compound, a squalene synthesis inhibitor, a fibrate compound, a LDL catabolism enhancer and an angiotensin converting enzyme inhibitor". PA0 2) JP-A H5(1993)-148196 describes that "a pharmaceutical composition comprising 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenyl acetic acid, or its precursor or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier" may contain "an anorectic, a vitamin, a hypotensive drug and an blood glucose lowering agent, for instance, sulfonylureas, biguanides and thiazolidinediones". PA0 3) Diabetes Frontier, Vol.8, p.499 (1997) describes that "CL316243 completely inhibited the weight gain in brown adipose tissues caused by troglitazone" when CL316243 (.beta. 3 adrenergic receptor antagonist) and troglitazone were administered to obese rats. PA0 4) WO93/3724 describes that 3-Guanidinopropionic acid (3-GPA) antagonizes in a dose-dependent manner the weight gain that occurs in obese, diabetic KKA.sup.Y mice that are treated with pioglitazone hydrochloride, an insulin sensitizing agent. PA0 5) Egypt. J. Pharm. Sci., vol.29, No.1-4, pp.355-366(1988) describes "interactions of some anorexigenic drugs with tolubutamide in normal and diabetic rats". PA0 6) WO97/27847 describes that "acetylphenols which are useful as antiobesity and antidiabetic compounds" can be used together with "fenfluramines, dexfenfluramines, phentiramines, .beta. 3 adrenergic receptor agonists". PA0 (1) a pharmaceutical composition which comprises an insulin sensitizer in combination with an anorectic; PA0 (2) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is a compound of the formula: ##STR1## PA0 (3) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is pioglitazone hydrochloride, troglitazone, rosiglitazone or 4-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]isoxazolidin-3,5-dione ; PA0 (4) a pharmaceutical composition according to the above (2), wherein the compound of the formula (I) or salt thereof is pioglitazone hydrochloride; PA0 (5) a pharmaceutical composition according to the above (1), wherein the anorectic is a central anorectic; PA0 (6) a pharmaceutical composition according to the above (5), wherein the central anorectic is mazindol; PA0 (7) a pharmaceutical composition according to the above (1), wherein the insulin sensitizer is pioglitazone hydrochloride and the anorectic is mazindol; PA0 (8) a pharmaceutical composition according to the above (1), which is for preventing or treating diabetes; PA0 (9) a pharmaceutical composition according to the above (8), wherein the diabetes is noninsulin-dependent diabetes mellitus; PA0 (10) a pharmaceutical composition according to the above (2), wherein the compound of the formula (I) or salt thereof is troglitazone; PA0 (11) a pharmaceutical composition according to the above (2), wherein the compound of the formula (I) or salt thereof is rosiglitazone or its maleate; PA0 (12) a pharmaceutical composition according to the above (1), which is for preventing or treating diabetic complications; PA0 (13) a pharmaceutical composition according to the above (1), which is for preventing or treating impaired glucose tolerance; PA0 (14) a pharmaceutical composition which comprises an insulin sensitizer and is used in combination with an anorectic; PA0 (15) a method for preventing or treating diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; PA0 (16) a method for preventing or treating diabetic complications in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; PA0 (17) a method for preventing or treating impaired glucose tolerance in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with an anorectic; PA0 (18) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetes which is used in combination with an anorectic; PA0 (19) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetic complications which is used in combination with an anorectic; PA0 (20) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance which is used in combination with an anorectic; and PA0 (21) a method for reducing the amount of an insulin sensitizer or/and an anorectic administered to a diabetic mammal, which comprises administering to said mammal an effective amount of them. PA0 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (generic name: pioglitazone); PA0 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)meth oxy]phenyl]methyl]-2,4-thiazolidinedione(generic name: troglitazone/CS-045); PA0 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedio ne(generic name: rosiglitazone/BRL-49653); and PA0 5-[3-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy]phenyl]propyl]-2,4-oxazolidin edione. PA0 (.+-.)-4-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]isoxazolidin-3,5 -dione (JTT-501) or its salt; PA0 5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazolid inedione (generic name: englitazone) or its salt (preferably sodium salt); PA0 5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thia zolidinedione (generic name: darglitazone/CP-86325) or its salt (preferably sodium salt); PA0 5-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazoli dinedione (CP-92768) or its salt; PA0 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31637) or its salt; PA0 4-[(2-naphthalenyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide (AY-30711) or its salt; PA0 5-[[6-(2-fluorobenzyloxy)-2-naphthyl]methyl]-2,4-thiazolidinedione (MCC-555) or its salt; PA0 (.+-.)-[5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromet hyl)phenyl]methyl]benzamido (AHG-255) or its salt; PA0 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethenyl]benzo ic acid (LGD1069) or its salt; PA0 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]n icotinic acid (LGD100268) or its salt; PA0 1,4-bis[4-[(3,5-dioxo-1,2,4-oxadizolidin-2-yl)methyl]phenoxy]-2-butene (YM-440) or its salt, etc.
These prior art references do not specifically describe or suggest combining an insulin sensitizer with an anorectic, and effects of such combination.
The origin of noninsulin-dependent diabetes mellitus (NIDDM) includes insufficient insulin action in the liver and peripheral tissues (insulin resistance) as well as insulin secretion deficiency in the pancreas. The onset of the insulin resistance is highly affected by the present satiety environment such as stress and obesity, and alimentotherapy is firstly employed for reduction of the insulin resistance. However, observance and continuation of the alimentotherapy is accompanied by mental pains of patients, and in many cases does not provide the expected results. Therefore, an insulin sensitizer is employed as a subsidiary drug for the alimentotherapy, and an anti-obesity drug is employed in obese patients.
The insulin sensitizer strengthens insulin action to lower blood sugar in diabetic patients.
In obesity, the number of insulin receptors in fatty cells themselves are reduced because of hypertrophy of fatty tissues, further, insulin resistance is strengthened by accelerated secretion of insulin resistance-causing cytokines such as TNF-.alpha.. Increase of the amount of required insulin accelerates insulin secretion in the pancreas. As a result, in most cases, obesity is accompanied by hyperinsulinemia or hyperlipidemia.
On the other hand, an anorectic do not result in lowering blood glucose in many cases, although they reduce body fat. The anorectic is known to possess side effects such as dependence, hydrodipsia, constipation, nausea, emesis, gastric discomfort, stomach flatulence, dizziness, palpitation, eruption, increase of GTO or GPT, sleep disturbance, etc.
Development of excellent drugs which are sufficiently improved as a medicine having an excellent diabetic treatment effect without apparent detection of side effects is desired.